One of the major problems in the management of the cancer patient is the predictability or determination of therapy response prior to the initiation of treatment. This can be particularly important for the patient receiving chemotherapy. The conventional approaches in the determination of the treatment protocol (to establish a treatment agent or drug(s) regimen) to be used in the treatment of specific tumor type remains largely empirical. That is, the conventional therapeutic approach is to utilize what is considered to be the most effective treatment as determined by prospective randomized trials across a sampled population. This approach overlooks the fact that, as each patient is different, so is each patient's tumor and/or response to the treatment selected. The biological and physiological uniqueness of each patient is not considered nor is the potential for an individualized therapeutic approach. See generally Kastrissios et al., Screening for Sources of Interindividual Pharmacokinetic Variability in Anticancer Drug Therapy: Utility of Population Analysis, Cancer Investigation, 19(1), 57-64 (2001).
Both the need for and potential benefits of a predictive test for a patient's response to a particular treatment protocol, particularly for the cancer patient, have long been recognized. The benefits include (a) an increased chance for tumor response from initial effective therapy, (b) a reduction in the potential for development of resistant cells when less effective therapy is given (c) a decreased morbidity associated with non effective therapy, and (d) an improved probability of cure or positive outcome with the timely administration of effective therapy. It is generally accepted that the initial treatment approach is the most important to obtain the best tumor response. Second and third line therapies are typically less effective and primarily palliative. Therefore, the availability of a method to determine the most appropriate and effective drug (s) prior to the initiation of therapy may allow for a maximum response. That is, if, for a given tumor, several drugs have been shown to be effective in large clinical trials, the question as to which one (s) to use in a particular patient can be important. Since, as noted above, differences do exist between individual tumors of the same site, choosing the most effective therapeutic agents should increase the likelihood of a beneficial response and reduce the chance for the development of a resistant cell population. It may also reduce the possibility of utilizing a particular drug as a second or third line therapy, when its effectiveness may be reduced because of the development of drug resistant populations.
An important additional benefit to the patient may be a lower morbidity rate than that which is associated with a “try and see” approach (that is, to “try” a specific regimen and “see” how the patient responds). A knowledge of effective drugs may reduce the morbidity of therapy, since it will offer the patient an increased chance for response and/or reduce the need for second and third line therapies.
The early attempts to establish predictive tests were dependent on the availability of cell culture techniques and cell lines. The tests included evaluation of cell morphology, exclusion of vital dyes, and incorporation of radioactive precursor molecules after incubation of tumor cells with anticancer agents. The primary problem was a lack of predictive value in most correlative studies. See, e.g., Yarnell et al., Drug Assays on Organ Cultures of Biopsies from Human Tumours, Br Med J 1964; 2:490-491. More recently, the culture of human tumors was reported by Hamburger et al., in Primary Bioassay of Human Tumor Stem Cells, Science 1977;197:461-463. Since its introduction, the Human Tumor Clonogenic Assay (HTCA) has been investigated as a predictive assay for human tumors. Contrary to the previously identified assays, inhibition of cellular proliferation is directly used as the experimental endpoint. In addition, it defines results in terms of chemoresistance and chemosensitivity. The cumulative results of over 2300 correlations between the HTCA and clinical response was reported by Von Hoff et al. in 1990. See Von Hoff et al., Selection of Cancer Chemotherapy for a Patient by an In Vitro Assay Versus a Clinician, JNCI 1990;82:110-116. The results revealed a 69% probability for a patient to have at least a partial response if the tumor specimen is sensitive to the drug in vitro. However, if the tumor is resistant in vitro, there appears to be a 91% chance for clinical resistance. The major technical problems with most clonogenic assays include the lack of growth in 40 to 60% of all specimens and a relatively long incubation time (generally on the order of at least 14 days) before results are available. In addition, there is insufficient data available on the effect of assay-guided chemotherapy on patient survival, and most clinically observed responses are partial responses.
More recently, a commercially available assay has alleged a 99% accuracy in prediction of clinical failure. The success of the assay purportedly results from extended exposure of the patient tumor cells to levels of chemotherapy agents, which approximate the peak plasma levels attained after conventional IV administration. If a patient's cells proliferate after extended exposure to peak plasma levels of chemotherapy agents, then it can be accurately predicted that these cells will also demonstrate resistance to normal exposures in vivo. However, the reported accuracy to predict chemo-sensitivity is only about 60-70%. Moreover, the assay method is not able to address tumor response over time or in real time. The sample represents the biology of only one point in time of the treatment history of each tumor; it does not consider conditions that effect drug delivery to the tumor, including poorly perfused tumors, local areas of hypoxia or acidosis and host-dependent resistance mechanisms which can cause high false-positive prediction of in vitro chemo-sensitivity. See Kem D H, Tumor Chemosensitivity and Chemoresistance Assays, Cancer, 79:7, 1447-1450, 1997.
Others have proposed alternative methods such as Single Photon Emission Tomography (SPECT) and Positron Emission Tomography (PET), which have been found to be useful for obtaining functional data of tumors when radiopharmaceuticals are utilized. There are several approaches for the assessment of chemotherapeutic effects that include measurement of tumor metabolism, quantification of pharmacokinetics of radiolabeled drugs and evaluation of multidrug resistance. A commonly used positron emitting radiopharmaceutical for oncological studies is F-18-Fluordeoxyglucose (FDG). FDG is a tracer, which parallels the transport and phosphorylation of glucose into the cell but is then trapped. Therefore, it is used as an estimate for the regional tumor glucose metabolism. In addition, FDG is a tracer that shows a preferential accumulation in most of the tumor types. As a result, therapy monitoring may be performed using multiple follow-up PET studies where a decrease in tumor uptake correlates with clinical response to therapy, and conversely an increase is indicative of tumor growth. PET can typically be utilized to measure the kinetics of the drug over a target area in normal tissue and in the vascular system. Generally stated, only 5FU (5-Fluorouracil) has been found useful for routine PET scanning. See Kissel et al., Noninvasive determination of the arterial input function of an anticancer drug from dynamic PET scans using the population approach, Med Phys 1999 April; 26(4):609-15.
In operation, the PET methodology may allow for the direct measurement of radiotracer concentrations and, thus, a quantification of the 5-[F-18]FU accumulation. Dimitrakopoulou et al., Studies with Positron Emission Tomography After Systemic Administration of Fluorine-18-Uracil in Patients with Liver Metastases from Colorectal Carcinoma, J Nucl Med, 1993 July, 34:1075-1081. When utilized to assess liver metastasis from the colon, kinetic data showed different distribution patterns for the metastases, the normal liver parenchyma and the vessels. The normal liver parenchyma has the highest 5-[F-18]FU uptake about 30 minutes after onset of the infusion of the tracer, followed by a decrease to 25% of the maximum at the end of the acquisition time. The uptake in the metastases was low and relatively constant during the 120-minute acquisition time. The mean uptake was one-third of the liver uptake at the same time interval. Two caveats associated with the distribution pattern reflect the difficulty in utilizing one (single) observation in determining effective therapeutic response. It was observed that the early 5-FU uptake is primarily determined by the intracellular uptake of non-metabolized 5-FU. Late 5-[F-18]FU uptake values, e.g., 120 minutes after onset of the 5-FU application, are used as a prognostic parameter for therapy response, since the data obtained from that time interval are most likely to mirror the therapeutically active fraction of the drug. In addition, 5-[F-18]FU studies demonstrated a great variability of drug uptake in liver metastases even in the same patient, which may explain the low response rates and the variability in response to therapy. The 5-[F-18]FU concentration as measured with PET prior to onset of 5-FU chemotherapy is predictive of therapy outcome, since only a high 5-FU trapping in the metastasis is correlated with regression, while low 5-FU concentration are not capable of preventing tumor growth during chemotherapy.
PET can also be used to study mechanisms of drug resistance by employing a combination of O-15 labeled water and 5-[F-18]FU. The former has been used to study the transport system and identified a difference between a passive and active energy-dependent transport systems. Enhanced 5-FU trapping was noted in 70% of these lesions. Since only tumor lesions with an energy-dependent transport system of 5-FU are likely to respond to 5-FU therapy, this information is believed to be of clinical value for the individualization of the therapeutic protocol. PET can be used to select those patients with metastases possessing an active 5-FU transport system, which can aid the oncologist to direct therapy by modifying the treatment protocol.
Multidrug resistance (MDR) occurs when cells appear to overcome the cytotoxic effect of chemotherapy. Cytotoxic drugs are rapidly eliminated, especially in cells with a high concentration of P-glycoprotein (Pgp), a transmembrane drug flux. Tumors from the colon, kidney, liver and pancreas frequently express the Pgp at high levels. Studies by Piwnica-Worms et al. reported on the use of Tc-99m-sestamibi, a synthetic organotechnetium complex, that can act both as a substrate for Pgp and can act as a marker for the expression of Pgp. See Piwnica-Worms et al., Functional Imaging of Multidrug-resistant P-Glycoprotein with an Organotechnetium Complex, Cancer Res 53, 977-984, 1993. A high Sestamibi accumulation in the tumor correlated with a low Pgp expression and a good prognosis for chemotherapy. Despite these advances and observations, there are limitations of PET methodology. Practically speaking, this evaluation method would potentially be available to only a limited number of patients since it can be time consuming, expensive and impractical for application, not only to every patient, but on multiple occasions. Secondly, PET scans cannot discriminate metabolites. In order to improve the interpretation of the PET data, Nuclear Magnetic Resonance Spectroscopy (NMRS) has also been used in some patients.
Following the observation in 1984 by Stevens et al., 5-Flourouracil metabolism monitored in vivo by 19F NMR, Br J Cancer 1984, 50:113-117, who showed that 19F-NMRS could detect 5-FU in the liver of mice, the work was extended to observations in the tumors of rats and mice. See Wolf et al., Tumor trapping of 5-fluorouracil: In vivo 19F NMR spectroscopic pharmacokinetics in tumor-bearing humans and rabbits, Proc Natl Acad Sci USA, 1990, January, 87:492-496. In 1990, Presant et al. reported their initial observations on the clinical experience with NMRS in 11 patients. They described a “trapped” pool of intra-tumoral 5-FU, defined as a pool of 5-FU whose disappearance half-life (T1/2) is longer than its T1/2 in peripheral blood. They also presented information on the correlation between the T1/2 of 5-FU in tumors and anti-tumor response to 5-FU. Generally stated, they found that the six patients with T1/2 of greater than 20 minutes responded to chemotherapy and that the converse was also true. More recently, Presant et. al., in Enhancement of Fluorouracil Uptake in Human Colorectal and Gastric Cancers by Interferon or by High-Dose Methotrexate: An In Vivo Human Study Using Noninvasive 19F-Magnetic Resonance Spectroscopy, J Clin Oncol 18:255-261; 2000, reported that the in vivo modulation of the tumoral pharmacokinetics of 5-FU could be measured non-invasively by 19F-MRS and; suggested that such information correlates with subsequent clinical outcomes. Further, they suggested that interferon (IFNa-2a) and high-dose methotrexate could increase the intratumoral 5-FU in some patients.
31P/NMR spectra contain peaks from nucleoside triphosphates (NTP), phosphocreatine (PCr), and inorganic phosphates (Pi) and can therefore provide information about tumor energy status. The potential of 31P/NMR spectroscopy for evaluating the effect of treatment (radiation and hyperthermia) on sarcomas has been studied by Dewhirst et al. Dewhirst et al., Soft-Tissue Sarcomas: MR Imaging and MR Spectroscopy for Prognosis and Therapy Monitoring, Radiology 174:847-853, 1990. They purportedly observed a relationship between treatment-induced decrease in ATP/Pi with the probability of development of necrosis and in a related study showed an increase in oxygenation after treatment correlated with the amount of tumor necrosis. Another example of an application of 31P/NMR spectroscopy is in the monitoring of biochemical inhibition of specific metabolic pathways. This inhibition is designed to enhance tumor response to radiation and chemotherapy. Agents such as 2-deoxyglucose, lonidamine, 6-aminonicotinamide (6AN) can inhibit biochemical pathways and enhance responses to chemotherapy and radiation. Koutcher et al. (in Koutcher et al., Potentiation of a Three Drug Chemotherapy Regimen by Radiation, Cancer Res 53:3518-3523, 1993) observed changes in spectra of mammary carcinoma before and after treatment with a 3-drug combination. The observed changes were used to determine the timing between the drugs and radiation based on when tumor metabolism was maximally inhibited. While the drugs alone induced no complete responses and radiation only induced a single (1/20) “complete response” (CR), the combination of the drugs and radiation (administered when the NMR data demonstrated maximal metabolic inhibition) yielded a 65% CR rate and a 25% durable (<1 year) CR rate, without further treatment.
Several groups have proposed the use of intraoperative radiation probes for the purpose of identifying cancerous regions in the body. See e.g., Zanzonico et al., The intraoperative gamma probe: basic principles and choices available, Semin Nucl Med 30 (1), pp. 33-48 (January 2000); Barber et al., Comparison of NaI(TI), CdTe, and HgI2 surgical probes: physical characterization, Med. Phys.; 18(3), pp.373-381 (May-June 1991); and Hoffman et al., Intraoperative probes and imaging probes, Eur Jnl. Nucl. Med. 26(8), pp. 913-935 (August 1999). These techniques can be characterized as belonging to one of two primary applications: radioimmunoguided surgery (RIGS) and sentinel node detection. It is believed that the RIGS applications may be generally described as radiolabeling an antibody specific to a target tumor and then probing in the operational field with a radiation detector to evaluate which tissue may be suspect. It is believed that this technique can provide better localization than is available with SPECT (Single Photon Emission Computed Tomography).
The sentinel node detection techniques can be described as using an injection of a radiolabeled substance -into a tumor and then recording or evaluating the “downstream” activity of the radiolabeled substance to determine the degree of lymph node involvement. A clinician can use a pen-like gamma probe to trace or detect the signal associated with the radioactivity of the lymph nodes (such as during a surgical procedure).
It is also known that there are changes in glycolysis in normal versus tumor cells. The facilitative glucose transporters (GLUT 1-5 and 7) have been reported as proteins that regulate transport of glucose from the blood to cytoplasm. These proteins are passive transporters and, thus, provide glucose to the interior of a cell if a concentration gradient exists. As previously suggested, increased uptake of glucose by cancer cells may be due to an up-regulation of the GLUT genes responsible for the proteins. Because transport of glucose by these transmembrane proteins is passive, the concentration in the cytoplasm is kept below the level in the interstitial fluid. This means that glycolysis can accelerate to keep up with the process and to attempt to maintain the desired internal cell level or transmembrane concentration gradient. Therapies that disrupt a key element of glycolysis may arrest the avid uptake of glucose by tumors by reducing the transmembrane concentration gradient. [18F]FDG has been used recently to look at alterations in glucose uptake following radiation therapy. This observation may be important in assessing the onset of apoptosis due to radiation exposure. Glucose transport has been studied after induction of apoptosis by gene therapy designed for a rat tumor model. [11C]glucose labeled in the 1 and 6 carbon positions was used to look at the “pentose cycle.” This cycle preferentially selects carbon in the first position and incorporates it into CO2. Thus, it has been proposed that the ratio of C1/C6 could be predictive of the staging of gliomas. However, this proposed evaluation method may be difficult in that there is a low (approximately 5%) amount of glucose entering the pentose cycle and because the evaluation method is performed in successive runs (first for C1 and then for C6) with a clinically challenging PET isotope.
Despite the foregoing, there remains a need to provide cost-effective and/ or alternative methods, systems and devices that can individualize and customize therapy to improve response and outcome and/or otherwise monitor therapeutic response or delivery of radiolabeled agents in the body. There is also a need for methods, systems and devices that can provide increased information on normal and/or tumor glycosis and/or the impact of therapies on same.